Tyrosine Kinase Inhibitors of BCR/ABL: Pharmacokinetic and Pharmacogenetic Study in Patients Affected by Chronic Myeloid Leukemia. Evaluation of Efficacy and Tolerability
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 412
- 试验地点
- 2
- 主要终点
- Percentage differences in Imatinib/Nilotinib pharmacokinetic parameters according to Solute Carrier (SLC) and ATB-Binding Cassette (ABC) transporters polymorphisms in chronic myeloid leukemia patients
研究概览
简要总结
Rationale
The pharmacokinetics of imatinib and nilotinib, two BCR/Abl tyrosine-kinase inhibitors (TKI), is variable among patients suffering from chronic myeloid leukemia (CML). Transmembrane transporters may play a pivotal role in interindividual variability in TKI disposition. Furthermore, minimum plasma concentrations (Cmin) higher than 1 mg/L could be associated with a higher likelihood of molecular and cytogenetic responses.
The TIKlet study is aimed at evaluating correlations among the pharmacogenetics, pharmacokinetics and treatment efficacy/tolerability of imatinib and nilotinib in CML patients.
- PATIENTS AND METHODS
1.1. Patients
Patients affected by CML will be enrolled after the informed consent will be signed, according to the following inclusion criteria:
- patients of both sexes,
- age between 18 and 80 years,
- treated with imatinib or nilotinib,
- included in follow-up activities at the participating Hematology Divisions,
- able to give informed consent,
- with a proved compliance with the scheduled treatment.
The administration of other drugs will be allowed, being known the dose and duration of treatment, as well as smoking and herbal products.
Alterations in organ functions or physicochemical exams, body mass index >28 do not represent exclusion criteria.
1.2. Enrollment and follow-up visits
During enrollment visit:
- patients will be informed about the study, their signed informed consent form will be collected and an individual alphanumeric code will be assigned.
- Patients' data will be recorded within the individual case report form (CRF) and a blood sample will be obtained.
At follow-up visits, a blood sample will be collected for therapeutic drug monitoring (TDM) and patients' CRF will be updated.
1.3. Blood samples
After centrifugation, the resulting plasma will be collected for TDM. During the enrollment visit, an aliquot of whole blood will be collected for molecular analyses.
1.4 Laboratory analyses
TDM will be performed by high-performance liquid chromatography systems, then results will be evaluated by a population pharmacokinetic analysis. Single nucleotide polymorphisms will be investigated in the following genes: ABCB1, ABCG2, hOCT1, OCTN1, OATP1A2.
Finally, response to drugs, in terms of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR), and tolerability will be evaluated. Any possible correlation among drug disposition, pharmacogenetics and treatment effects will be analyzed.
详细描述
- Patients
1.1. Patients
CML patients will be included according to the following inclusion criteria: a) patients of both sexes, b) age between 18 and 80 years, c) treated with imatinib or nilotinib, d) included in the follow-up in the Divisions / Units of Hematology involved in the project e) able to give informed consent to trial participation, f) with a proved compliance with the scheduled treatment.
Patients will be excluded from participation to the study if: a) age <18 or >80 years or b) unable to provide informed consent. The inability to attend the follow-up visits will not be considered an exclusion criterion from the study. In this case, collected data will be used in pharmacokinetic and statistical analyses on the basis of an intention-to-treat criterion.
The following conditions should be noted:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients affected by chronic myeloid leukemia
- •Age limits: 18-80 years
- •Male and female patients
- •Treatment with imatinib/nilotinib since at least 3 weeks
- •Optimal adherence
- •Signed informed consent
排除标准
- •Age <18 or >80 years
- •Poor adherence
- •Inability to attend follow-up visits
- •Lack of signed informed consent
- •Concomitant administration of other drugs will be allowed, but active pharmacological agents, their dose and duration of treatment should be recorded.
- •Smoking is not considered an exclusion criterium, but it should be noticed and recorded
研究组 & 干预措施
CML Imatinib/Nilotinib
Patients affected by chronic myeloid leukemia and treated with imatinib or nilotinib
干预措施: Imatinib/Nilotinib (Drug)
结局指标
主要结局
Percentage differences in Imatinib/Nilotinib pharmacokinetic parameters according to Solute Carrier (SLC) and ATB-Binding Cassette (ABC) transporters polymorphisms in chronic myeloid leukemia patients
时间窗: 2 years
Percentage difference in drugs pharmacokinetic parameters (apparent clearance \[CL/F\], minimum plasma concentration at steady state \[Cmin,ss\], area under the time concentration curve \[AUC\], terminal elimination half-life \[t1/2\]) according to polymorphisms of SLC and ABC transporters (wild-type homozygous vs. heterozygous and polymorphic homozygous patients)
次要结局
- Time-to-CCyR or Time-to-MMR and Cmin,ss values or SLC / ABC genotype(2 years)
- Number of patients with Adverse Drug Reactions and Cmin,ss values or SLC / ABC genotype(2 years)
- Time to Complete Cytogenetic Response (Time-to-CCyR) and Major Molecular Response (Time-to-MMR)(2 years)
- Percentage of patients who achieve MMR/CCyR and Cmin,ss values or SLC/ABC genotype(2 years)
研究者
Antonello Di Paolo, M.D., Ph.D.
Associate Professor of Pharmacology
University of Pisa